How to modulate chemical structure of polyoxazolines by ...

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1

How to modulate chemical structure of polyoxazolines by
appropriate functionalization


Brieuc Guillerm, Sophie

Monge, V
incent

Lapinte
,
* Jean
-
Jacques

Robin


Institut Charles Gerhardt Montpellier UMR5253 CNRS
-
UM2
-
ENSCM
-
UM1
-

Equipe Ingénierie
et Architectures Macromoléculaires, Université Montpellier II


Bat 17


cc1702, Place Eugène
Bataillon 34095 Montpellier Cedex 5


Corresponding author:
Vincent.Lapinte@univ
-
montp2.fr
;
Tel: 33
-
4
-
67
-
14
-
48
-
32; fax: 33
-
4
-
67
-
14
-
40
-
28.




2

Abstract

Polyoxazolines (POx
) are increasingly studied as polymeric building blocks due to the possibility
of affording tunable properties. Additionally,
as
it was proved that biocompatibility and stealth
behavior of POx are similar to that of poly(ethylene
glycol) (PEG
)
,

it became c
hallenging to
develop polyo
xazoline
-
based (co)polymers. Even if POx have a lot of advantages, they also show
an important drawback as it is to date impossible to prepare high molecular weight
polyoxazolines, with low polydispersity indexes. So, i
t appears
important to judiciously
functionalize them. This review covers the multiple ways of functionalization of polyoxazolines.
The use of functional initiators, functional terminating agents
,

and 2
-
R
-
2
-
oxazolines with R
functional side group is detailed. In con
clusion, some perspectives on
POx

functionalizations are
also reported, with functions permitting selective

“click”

reactions.


Keywords:

cationic polymerization; functionalization of polymers; oligomers; ring
-
opening
polymerization




3

1.
Introduction

Polyoxazolines (POx)
represents nowadays a valuable type of macromolecules for many reasons.
For instance, they are considered as bio
-
inspired polymers as they are structural isomers of
both
polyacrylamides, with a pendant amide function, and polypeptides,

bearing amide function in the
main chain
.
[
1
]

To date, they were mainly investigated toward bio
medical applications
[
2
,
3
]

due to
their biocompatibility, biodistribution, blood clearance and

protein adsorption.
[
4
-
8
]

Based on their
low toxicity, poly(
2
-
oxazolines) are anticipated to be suitable to build antimicrobial materials,
when associated with quaternary ammonium salts. They are also employed as drug carriers, for
instance.
For all these reasons, POx are considered as similar to po
l
y(ethylene
glyc
ol
)

(PE
G
)
.

I
t is
also
important to notice that t
he latter
showed important drawbacks
.
[
9
,
10
]

Indee
d, it was notably
shown that PEG

leads to adverse side effects in the body, caused by the polymer itself or by side
products

which

are toxic
. Unexpected pharmacokinetic behavio
r can also occur with PEG
-
based
carriers.

T
hese
non negligible
problems led to the development of polyoxazoline derivatives
which are today

considered as a

valuable

alternative

to PE
G
.

Other important characteristic of
POx
-
based

ma
terials is their thermosensitivit
y as some of them have a lower critical solution
temperature (LCST), depending on the R group of the pendant chain.
[
11
]

T
hermoresponsiveness is
often used to build drug carriers,
[
12
]

and until now the most studied thermosen
sitive polymer in
the literature is poly(N
-
isopropylacrylamide) (PNiPAM) as
its
LCST (around 32 °C) is relatively
independent of environmental conditions.
As

PNiPAM is not proved to be biocompatible
,

POx
may

replace it and
,

additionally,
the LCST value
of such polymers
can be modulated

from 5 to 90
°C

as a function of the R group of the pendant chain
,

which is a great advantage.

Well
-
defined
POx
s

are

easily
prepared
by cationic ring
-
opening polymeri
zation
(CROP)
of cyclic
2
-
R
-
2
-
oxazolines and various properties
are

obtained as a function of the nature of the R pendant
4

alkyl
chain
(
Me, Et, Pr,
etc.
).
Several teams
demonstrated

the effect of the
R
side

group

on the
properties in solution

such as

solubility in the common solvents

and/or

water
,
and
the
presence of
a
low
er

critical solution temperature (
LCST
)
.

The
influence

of the R group
s

was also examined
in
solid state

with the determination
of

mechanical
[
13
,
14
]

and thermal
[
15
-
18
]

properties.

Whereas POx
s

are

very promising materials
,
one of their drawbacks appears

to be
very restrictive
. Indeed,
whatever
the
nature of 2
-
oxazoline monomer and the initiator
,
the molec
ular weight of well
-
defined POx with low polydispersity index,

usable for smart applications, is only limited to about
40 kg.mol
-
1

(
Table 1
)
.

Low molecular weight is an important limitation for the spread
development of polyoxazolines in comparison with poly(ethylene glycol) (PEG) competitor
(notably in terms of biocompatibility and stealth behavior) which can be prepared with very high
molar m
asses. For this reason, functionalization appears to be the key parameter to overcome this
problem. One of the benefits of POx is the possible functionalization of the lateral chain, which is
impossible in the case of PEG. Additionally, POx has also the gr
eat advantage of being easily
converted to polyamines by treatment in acidic medium.

In the case of
2
-
oxazoline bearing alkyl
chains
,
no relation between the nature of the side group and the maximum molecular weight was
found
.
A

lot of
studies

mention

transfer reaction
s

as
explanation

of limited molecular weight but
only a few of them investigate
s

in detail
s

this side
reaction.
Lévy and

Litt
[
19
]

as well as Kourti
,
[
20
]

in the
particular
case of initiator based on metallocene
,

proposed a

monomer transfer
reaction
based on the abstraction of the

-
proton
of monomer and its
transfer
on
the terminal oxazolinium
specie
s

of the propagating polymer chain
.

Schubert et al. illustrated the transfer reaction in the
case of
2
-
ethyl
-
2
-
oxazoline using

matrix assisted laser desorption/ionization
-
time of flight
(MALDI
-
Tof)

experiments.
[
21
]



5

INSERT TABLE 1


In order to increase the molecular weight and decrease the reaction time
, t
he polymerization of
various 2
-
R
-
2
-
oxazolines was achieved
by Schubert
et al
.
[
22
,
23
]

us
ing

microwave
s
.
The

latter,
combined with an increase of the reaction temperature,
allowed decreasing
the reaction time

but
did not lead

to higher molecular weights
.
[
24
]

Indeed
, the synthesis of longer well
-
defined polym
er
chains in a living way fails

as the average molecula
r weight distributions broaden

f
or
polymerization degrees
higher than 300
.

As a consequence, to extend the properties of low
molecular weight polyoxazolines, the

onl
y solution
is

to functionalize them with appropriate
reactive groups in order to further extend their molar mass by combina
tion with other
polymers
[
25
]

or to add specific molecules to change some of their properties
.

For instance,
it was
proved that
antimicr
o
bial activity and hemocompatibility
of telechelic poly(2
-
methyloxazoline
)
i
s
greatly influence
d

by the

nature of the end groups.
[
26
]

F
unctionalization of the

POx

chain

end
s

i
s
obtained

by

using

functional initiators
[
27
]

or
terminating agents
[
28
]

or
via

the use of

2
-
R
-
2
-
oxazolines where R
represents

a

functional
pendant
group
[
29
]

(Figure 1)
.

It is also important to notice that
functional groups of initiator or monomer
interfere

in some cases

with

the
cation
ic
ring
-
opening polymerization

of 2
-
R
-
2
-
oxazoline.
[
30
]

This
usu
ally detrimentally
affect
s

yields and
the
control
of molecular weight and
such problems
are

minimized by using appropriate protecting groups on initiator

(P’ for protecting group in Figure
1)
, terminating agent or R pendant group

(
P

for

protecting group in Figure 1
)
.
This protection
strategy notably reduce
s

or remove
s

the nucleophilicity and basicity of
the
reactive sites

by steric
hindrance and / or electronic effects.

Indeed
,

the cationic character of the polymerization

process

6

is influenced by all nucleop
hilic reagents in the reaction

medium coming from impurities like
water, by
-
product
of

the initiator or
competing

nucleophilic site.


INSERT FIGURE 1


To develop smart applications, it is important to prepare well
-
defined polyox
azolines with
controlled functionality and molecular weight, and the appropriate functional groups at the chain
ends or along the backbone.
[
31
]

In this review, we describe functionalized polyoxazolines
suitable
for the preparation of well
-
defined polyoxazoline
-
based
(
co
)
polymers.
Functionalized

polyoxazolines
can be

obtained using appropriate
functional initiators, terminating agents and
pen
dant chains of 2
-
R
-
2
-
oxazolines. These different molecules
are

l
isted and

the choice in the
functional groups
is

discussed knowing that

some
protecting

groups
are

able to

push
back
the
limits

of incompatibility between functional reactants and CROP process
.

The functionalizat
ion
reactions are essential
as it will allow

the development of innovative materials

based on
polyoxazolines
. Even if lots of examples
are

reported in the literature, some interesting
perspectives can
also
be envisaged and will be

discussed
at the end of

this contribution.


2
.
I
nitiator
-
based
functionalization

To date, the cationic ring
-
opening polymerization of 2
-
oxazolines has been accomplished using
many i
nitiators including Lewis acids

such as boron trifluoride

(BF
3
-
OEt
2
)

(IIIa column of
periodic table
,
Figure
2
)
[
32
]

zirconiun/tris(pentafluorophenyl)borate,
[
20
]

trihalogenobismuthine,
[
33
]

7

and alkyl ester
s such as tosylates, triflates

(VIa column of
p
eriodic
t
able
,
Figure

2
)

and halides

(V
II
a column of
periodic table
,
Figure
2
)
. Th
e alkyl halide initiators range

from chloride
,
[
34
]

bromide
[
35
]

to iodide
[
36
,
37
]

as well as acetyl ha
lide.
[
38
]

The alkyl iodide initiators
a
re mostly
converted
in situ
from chloride
[
39
,
40
]

or bromide
[
41
]

analogues using NaI or KI reactants.
Th
e
simplest iodin
e
initiator
is

the molecular iodine

for which

the mechanism of polymerization has
recently been elucidated
.
[
42
]

Aoi et al
.

have

extensively
studied

the influence of the nature of the
initiator on the mechanism of polymerization which can be ionic and/or covalent
.
Chemical
structure of the initiator

also influence
s

the control

of the molecular weight
.
Indeed
it
wa
s

shown
that
a lack of control

with th
e persistence of residual initiator until the end of the polymerization
as well as

sometimes
a latency period at the beginning of the polymerization

is

observed

with
some of
the initiators
,

as demonstrated in the case of
4
-
(
p
-
toluenesulfonate)methyl
-
1,3
-
dioxolan
-
2
-
one,
[
43
]

3
-
butynyl tosylate
,
[
34
]

tosylate and triflate

initiator
s based on sugar
,
[
44
]

and
macroinitiators such as

-
methoxy
-

-
4
-
toluene
-
sulfonate poly(ethylene oxide)
.
[
45
]

An alternative
approach to overcome a slow initiation consists in
preparing first

the propagating species
composed of the initiator after reaction with one oxazoline monomer unit. It was widely shown
that this oxazolinium compound favor
s
the control of the polymerization related to the precursor
initiator.
[
46
]


-
F
unctionalized POx

we
re
also developed
. Either the functional group
carried

by the
initiator d
o
es

not react during t
he polymerization or it provokes

transfer reaction
s
. In the latter
case
,

a
protecting step i
s
first
required.
[
30
]


INSERT FIGURE 2


8

The cationic ring
-
opening polymerization
process
i
s compatible with a lot of
functions

based on
atoms
of

IVa column of the periodic table including carbon and
silicon

(Figure
2
).
The most
studied initiators
have
got

alkyl chains of various lengths
[
22
,
36
,
37
,
47
-
49
]

as well as
perfluorinated

chains.
[
28
,
50
]

T
he
compatibility also exists

with
unsaturated aliphatic
initiators with double
[
51
-
53
]

or
triple bond
s
[
34
,
54
,
55
]

even if

transfer reactions appeared above 50% conversion

in the latter case
.
These unsaturated groups have

an interest

because they
can

be involved

in
two types of

click


reaction
:

thiol
-
ene coupling

(TEC)

and

copper catalyzed azide
-
alkyne cycloaddition

(CuAAC)

named H
uisgen’s cycloaddition
. These reactions allow

the

modif
ication of
polyoxazoline
chain
end
s
[
1
]

and the synthesis of

amphiphilic block
copolymers by polymer
-
polymer coupling.
[
54
]

Initiators bearing
acetal, oxirane,
[
56
]

cyclocarbonate
,
[
43
]

ester
[
41
,
57
]

and silane
[
58
,
59
]

derivatives

also
lead

to the
CROP of oxazolines without any side reactions

(Figure
3
)
.
Macroinitiators d
erivi
ng
from

cholesteryl
[
56
]

and
vegetable oils as castor oil
,
[
57
]

diacylglycerol
,
[
56
]

1,2
-
o
-
diooctadecyl
-
sn
-
glyceryl
[
48
]

are

employed in the synthesis of amphiphilic
copolymers
.

The CROP of 2
-
oxazoline
is

also compatible with bis
-
initiators
bearing
unsaturat
ions

like acetylenic

groups
[
55
,
60
]

and
double
bonds.
[
52
,
61
,
62
]

Multi
-
functional initiators
based on
alkyl chain
s
,
[
61
,
63
,
64
]

aromatic

rings

with
t
wo
reactive sites in ortho, met
a or para position
s
[
52
]

or six

reactive sites
[
65
]

are

used in

the elaboration
of more
complex

structures
.
Other multi
-
initiators
a
re

described such as t
etrachloro or
iodoinitiators from porphyrine.
[
66
]


INSERT FIGURE 3


9

Otherwise,
some functional initiators need
the
protecti
on of their competitive reactive sites

such
as
alcohol, thiol
, or

amine

groups

(Figure
4
) which
can

interfere

during the CROP process
. These
functions
are

based on
heteroatoms belong
ing

to Va and VIa columns of the periodic table

(Figure
2
)
.
In initiator structure, the amine function
i
s

converted into urethane
,
[
49
]

quatern
ary

ammonium salt
[
26
]

whereas
thiol

i
s transformed into thi
o
ether.
A
lcohol

group
s

are

converted into
ester
group
s

including

adamanty
l which
leads
to
supramolecular network by interactions,
[
67
]

or
into

acetal or cyclocarbonate groups
.
Another
protec
t
ing group of alcohol
function i
s the

silyl
ether
s
like

the

ter
t
-
butyldiphenylsilyl ether
.
[
30
]

Alcohol groups
are

also

protected into acetate
group
s

in the synthesis of glyco
-
initiator.
[
44
]

Finally, s
ome initiators b
ear

polymerizable groups
such as
vinyl
[
68
]

and

styrenic
[
69
]

groups

in or
der to further elabo
rate graft

copolymers
.


INSERT FIGURE 4


3.
T
erminating agent
-
based functionalization

The cationic
nature

of the oxazoline polymerization and the persistence of the
oxazolinium
propagating specie
s

in terminal positi
on of the polymer chain require

a
nucleophilic reagent as
terminating agent

to stop the propagation
.

Several reactants based on sulfur, ox
ygen and nitrogen
chemistries we
re already described

as illustrated in Figure
5
.

The

terminating agents

belong to Va
and VIa columns of
the
periodic tab
le (Figure
2
).
The most
widely used terminating agent i
s
water
[
47
,
70
,
71
]

or
above all
its activated corresponding ion: hydroxyl ion in methanolic
sodium
hydroxi
de
solution
[
72
]

or sodium hydrogen carbonate
.
[
73
]

In this
particular
c
ase, whatever the
activated species
,

a hyd
roxy
-
terminated polyoxazoline i
s obtained but the mechanism of the
10

terminating stage is not the same. Indeed,
in the presence of

sodium hydrogen carbonate,
attack
on the 2
-
position
of the oxazolinium

ring occurs while attack of nucleophilic reagent takes place
on
the 5
-
position of
the
oxazolinium specie
.
[
74
]

T
he
other
main family
deals

with

amines which
ha
ve

an adequate nucleophilic
character

(
pKa>10
)

to react
with oxazolinium specie
s
.

The bas
ic
nitrogen derivative, ammonia
,

i
s
successfully used as terminating agent
[
75
]

while the primary
amines
are

the most important group
,

ranging from aliphatic

compounds

with long chain

to
obt
ain amphiphilic copolymers,
[
76
]

aniline
[
51
]

to

various functional primary amines.
[
69
,
77
]

Secondary cyclic amines as terminating agents
a
re represented by

piperidine,
[
78
]

piperazine
derivatives
[
39
,
79
]

or morpholine
[
80
]

and by bis
-
functional acyclic amines.
[
81
,
82
]

Even if the tertiary
amines
such as pyridine
,
[
56
]

pyrrole
[
35
]

and linear amine with long alkyl chain
ar
e less reactive
th
an those less substituted, they

react

as terminating agents
for

biocide applications
.
[
83
]

A
interesting
nitrogen
terminating agent
is

sodium azide (
NaN
3
)

which further le
a
d
s

to
Huisgen’s
cycloaddition to generate amphiphilic copolymers

by click reaction
.
[
63
,
84
]

Another approach
con
sist
s

in the use of bis
-
terminating agent like ethylenediamine

in
excess
t
o avoid the coupling
between two polyoxazoline chains
.
[
26
]

Functional amine with alcohol group

in

-
position
is

also
employed to obtain hydroxy
-
terminal polyoxazol
ine without
using potassium hydroxide,
prevent
ing

from the hydrolysis of
the
ester group
of

the initiator structure.
[
67
]

Another class of
terminating agents
is

based on sulfur
derivatives
like
sodium

thiolates
,
[
85
-
88
]

notably allowing
the
introduction of carboxylic acids,
[
88
]

for instance,
or on

carboxylic
acids and corresponding
carboxylate
salts

such as acrylic acid,
[
87
,
89
]

me
thacrylic acid,
[
90
-
92
]

maleic acid,
[
93
]

glutaric acid,
[
94
]

cinnamic acid
[
95
]

and terep
htalic acid
.
[
90
]

As explained in the case of functional initiators, functional terminating age
nts
are

employed to
transform

polyoxazolines in macromonomers
for

the further elaboration of grafted copolymers.
11

The polyoxazoline macromonomers belong to
styrenic,
[
39
,
96
]

acrylate
[
89
,
97
]

and

methacrylate

families
.
[
77
,
91
,
92
]

The last class of terminating agents gather
s

difunctional reagents which
permit

the increase of the
polyoxazoline
molecular weig
ht

by
a

double reaction

with central unsaturation
coming from the agent
.
[
90
,
93
,
94
]


INSERT FIGURE 5


4.
Functionalized m
onomer
s

The third method of
polyoxazoline

functionalization
corresponds

to
the use of
2
-
R
-
2
-
oxazoline
monomer bearing
R
functional pendant group

(Figure
6
)
. This possibility of functionalization
i
s
a
major

benefit

related to
poly(ethylene
glycol
)

and
offer
s

a
supplementary
scope
of
properties in
comparison
with

the
latter
.

In this
purpose
,

Hoogenboom

et al.
investigated the feasibility of the
preparation of various 2
-
substituted 2
-
oxazolines
as well as

their polymerization.
[
98
]

Whatever the
R group,
the side chain of the monomer may not react
during the CROP process.
C
onsequently
,

a
protecting
group

has to

be

used when necessary

to avoid
any side
-
reaction of R group
with

the
propagating specie
s
.
T
he R pendant group
s

b
ased on carbon and
silicon

(IV
a column of
p
eriodic
table, Figure
2
)
d
o
es

not
require

masking

groups.

A lot of 2
-
oxazolines bearing hydrocarbonated
pendant groups were developed while few 2
-
oxazolines with silane pendant chains were
sy
nthesized.
[
99
,
100
]

The most
studied

2
-
oxazoline
monomers
b
ear

linear
alkyl chain
with

various
length
s

ranging from
methyl

to undecyl group
s.
[
19
,
71
,
75
,
99
,
101
-
105
]

Additionally
, the alkyl chain
can
also be

substituted
,
with

iso
-
propyl,
[
75
]

iso
-
butyl,
[
103
]

ter
-
butyl
,
[
106
]

neopentyl
,
[
107
]

ethylheptyl
[
102
]

and

ethylpentyl

groups
.
[
108
]

T
he influence of R alkyl group on the polymer solubility, mechanical

12

(Young modulus)

and thermal properties

(glass transition temperature value) properties
of the
final mater
ial

has widely been described in the literature.
Poly(
2
-
methyl
-
2
-
oxazoline
)

and
poly(
2
-
ethyl
-
2
-
oxazoline
)
are

hydrophilic
[
16
]

whereas

longer R group
s

or aromatic group
le
a
d to
hy
drophobic character
,
[
107
]

reflecting

the importance of R
pendant chain

on the solubility.

G
lass
transi
tion temperatures

range

from 15 to 105

°C
as a function of the R chain length
.
[
15
-
18
]

Otherwise
, the Young modulus
is

only influence
d

by R group
s
containing less than four
carbons.
[
13
,
14
]

The impact of

the alkyl chain on the behavior of polyoxazoline in solution
is

also
illustrated by the existence of a LCST between
5

and
9
0 °C
[
15
,
18
,
109
]

which
i
s observed for most
POx, except for 2
-
methyl
-
2
-
oxazoline.

2
-
Oxazoline monomers bearing
u
nsaturation
a
re

described

with
single

(internal or terminal)
[
98
,
103
,
110
]

or several double bonds
such as
2
-
isopropenyl
-
2
-
oxazoline
[
92
]

which
polymerizes
under
free,
[
111
]

controlled (RAFT) radical processes,
[
112
]

anionic and cationic polymerizations
.
[
113
]

2
-
(9
-
Decenyl)
-
2
-
oxazoline

was modified by thiol
-
ene coupling in
the
presence of 2
-
mercaptoethanol
giving polyols

for polyurethane formulations.
[
110
]

The unsaturations of s
oy
-
based 2
-
oxazoline
monomer

were employed to cros
slink
the core of
micelles
under UV
-
irradiation
.
[
114
,
115
]

The same
strategy
i
s used with tetrathiol in order to elaborate
novel photoresist
.
[
116
]

Alkyne
-
based
oxazolines with one or two unsaturations
are

also described

and employed
for Huisgen’s CuAAC
cycloaddition
.
[
79
]

For instance,
Schlaad
et al.

investigated the crosslinking of block cop
olymer
micelles
by thiol
-
yne reaction.
[
117
]

Several
2
-
oxazolines

bearing cycloaliphatic R side chains
were
described with strained cycle
,
[
118
]

bicycle
or

tricycle.
[
98
]

2
-
Oxazolines with
aromatic R
side
groups

were
also
synthesized
[
19
]

with
various
substituents
[
29
,
98
,
105
,
119
]

including
perfluoro
group
.
[
103
,
120
]

Other aromatic systems were investigated with furanyl
[
103
,
121
]

and carbazoyl cycles.

13

As illustrated in Figure
2
, the mono
-
halogenated derivatives based on the
elements

of
the
VIIa
column of the periodic table c
an
not be considered as pendant chain due to
their

high reactivity as
initiator
which

can

make them react, thus
build
ing

branched polyoxazolines. More
over no
protecting group exists

with easy deprotection protocol

for such compounds
.
From the V
a

column
,

only
few
examples

of pendant chain

bearing
nitrogen
or
phosphorus
atoms
are

detailed
in the literature because of
their

high reactivity requiring a protecting step with
tert
-
butyloxycarbonyl (Bo
c
)

group
[
98
,
119
]

and into phosphoric ester
, respectively
.
[
98
]

Several examples
of pendant chains bearing nitrogenat
ed cycle
are

described with azetidinyl, azepanyl, piperidine,
1
-
azocanyl, 1
-
morpholine, 1
-
pyrrolidinyl
[
122
]

and pyrrolidonylethyl.
[
123
]

After the
hydrocarbonated R side groups, the
oxygenated
ones
are

the most numerous examples in the
literature
whereas

those

based
on sulfur

are

rare
[
103
]

(VIa column of periodic table, Figure
2
).

Alcohol end group
[
104
]

on the pendant chain was investigated even if a protecting group was
usually used such as ester
[
104
]

or acetal group
,
[
98
,
123
]

sometimes cyclic.
[
124
]

An interesting
example
is

the glycooxazoline
on which each alcohol group
is

protected into acetate groups.

The last class
of R side groups in
2
-
oxazoline
is

represented by polymer chains like
polystyrene
,
[
15
-
17
]

poly(ethylene oxyde)
[
123
]

and poly(

-
caprolactone)
.
[
125
]

These 2
-
oxazolines
are

employed

as
macromonomers in the
synthesis

of

graft

copolymers.


INSERT FIGURE 6


5. Conclusion and
Perspectives

14

In this review,
we described the different ways of functionalization of
polyoxazolines using
appropriate initiator, terminating agent or
via

the R group of the pendant chain of the
2
-
R
-
2
oxazoline monomer.
I
t

was shown that initiators can bear polyhedral oligomeric silsesquioxane,
saccharide, steroid, vegetable oil derivatives
,

for instance. T
erminating agents
can notably
allow
the introduction of
a polymerizable groups or sol
-
gel precursors

at the chain end
. The
wide
number of functionalizations of polyoxazolines also c
o
me
s

from R functional pendant groups in
the 2
-
R
-
2
-
oxazoli
ne monomers notably with glucose units, aromatic or fluorescent groups.
All
these possibilities
permit the easy synthesis
of very different polyoxazolines with lots of different
properties which can be adapted to the targeted application
,

often in the biom
edical field due to
the biocompatibility and stea
l
th
behavior

of POx.

Easy functionalization explains the interest
brought to polyoxazolines by the researchers who
noticed

a great contribution of these materials
compared to poly(ethylene glycol) which
proved these last years to generate some problems for
biomedical applications as explained in the introduction of this review
. Additionally, in the case
of PEG,
functional groups cannot be introduced so easily.
On the reverse,

functionalizations

of
POx

le
a
d to further reactivity
and permit

the building of more complex macromolecular
architectures by polymer
-
polymer coupling or by using polyoxazoline derivatives as
macroinitiators.

Among all possibilities of functionalization

of POx
,
selective and orthogonal

reactions named
“click
” reactions

appear

to be of interest

and were already successfully employed

in
macromolecular chemistry
.
[
126
]

More precisely
,
POx functionalizations have already been
described in the literature
using

thiol
-
ene
[
127
]

and

thiol
-
yne
[
11
7
]

reactions,
and the Huisgen’s
cycloaddition catalyzed by copper (CuAAC) reaction
.
[
79
,
128
]

In such cases, polyoxazolines
bear

double, triple bonds, or azido

groups (Figure 7).


15

INSERT FIGURE 7


Another example
involving
POx deals with a multifunctional copoly(2
-
oxazoline) containing

-
anthracene and ω
-
azide termini as well as pendant alkene group in the side chain (Figure 8).
[
128
]

In

that case, three different “
click
” reactions

are

achieved: (i) azide
-
alkyne cycloadditon, (ii)
Diels
-
Alder reaction, and finally (iii)
thiol
-
ene reaction.

This example is very interesting as it
shows that multi functional polyoxazolines can be prepared leading to complex chemical
structures with a very good control over the molecular weight of the p
olymer.


INSERT FIGURE 8


From works already described in the literature, some perspectives for the development of new
functionalized polyoxazolines can be considered
, based on “click” reactions

(Figure 9)
. Indeed,
from multi
-
functional POx

just described, it is obvious that Diels
-
Alder “click”
must be studied,
taking into account previous work reported by Saegusa
[
129
]

and Stevens
.
[
130
]

The great interest of
the Diels
-
Alder reaction is that it is reversible as a function of the temperature
. So
,

t
hermoreversible Diels
-
A
lder

reaction

could lead to the release of

polyoxazoline bearing
unsaturation
in terminal or pendant groups
.
[
131
]

Thus, new polyoxazolines bearing diene ha
ve

to
be prepared to react with
a dienophile. On the other hand
,

POx dienophile has already been
synthesized and could react with diene.
Another possibility consists in developing
“pentafluoro”
clicking, as already mentioned in the literature for other kinds of polymers.
[
132
]

This reaction
16

corresponds to the “clicking” of thiol with p
entafluoro groups, the latter being introduced via the
initiator of in the pendant chain of the oxazoline monomer (Figure 9).


INSERT FIGURE 9


These perspectives demonstrate that the synthesis of various polyoxazoline
-
based (co)polymers

is
still possible,
by using already prepared
polyoxazolines

or new
ones

with useful functionalities.
These new structures
might

lead

to innovative materials
that

could be employed for smart
applications, notably for the biomedical field

which require
s a

g
ood control
over the molar mass
and
the molecular weight distribution
,

and
also
appropriate functionalities
.




17

Figure
Caption
s


Table 1.

Limited molecular weights of polymer chains for various oxazoline monomers allowing
the obtaining of well
-
defined
polyoxazolines with low polydispersity indexes.

Figure 1.

General synthetic considerations for the synthesis of functionalized polyoxazolines
(Ini: initiator, T: terminating agent, P and P’: protecting groups).

Figure 2.

The
terminating agents and
the
pend
ant chain
s

of oxazolines
bearing various elements
of the periodic table
as well as
the nature of the initiators.

Figure 3.

Functionalized initiators for the cationic ring
-
opening polymerization of 2
-
R
-
2
-
oxazolines.

Figure 4.

Initiators bearing additional
protected and unprotected groups.

Figure 5.

Terminating agents for the cationic ring
-
opening polymerization of 2
-
R
-
2
-
oxazolines.

Figure 6.

R side groups of 2
-
R
-
2
-
oxazoline allowing the functionalization of POx pendant
chains.

Figure 7.

Polyoxazolines

bearing functional groups allowing “click chemistry” reactions (All
chemical structures were employed in “click” reactions except azido
-
containing polyoxazoline
with aromatic ring, as mentioned).

Figure 8.

Chemical structure of multi
-
functionalized poly(2
-
oxazoline) allowing the
incorporation of residues by three orthogonal “click” reactions (Diels
-
Alder, thiol
-
ene reactions,
and azide
-
alkyne cycloaddition.
[
128
]

18

Figure 9.

Perspectives concerning the synthesis of functionalized polyoxazolines from precursors
bearing appropriate functionality.



19

Table 1.

Limited molecular weight
s

of polymer chain
s

for various oxazoline monomers

allowing
the obtaining of well
-
defined polyoxazolines with low polydispersity indexes
.


R

DP
n,exp

M
n,max

(g.mol
-
1
)

Ð

Me
[
83
]

149

13000

1.04

Et
[
38
,
133
]

404

40000

1.20

Pr
[
134
]

106

12000

1.04

i
Pr
[
75
]

86

100
00

1.02

Bu

100
[
14
]

13000

1.20

Pent

14000

Hex

15000

Hept

17000

Non

20000

Ph
[
73
]

51

8000

1.31



Ð
:
poly
dispersity index.




20



Figure

1
.

General synthetic considerations for
the synthesis of
functionalized

polyoxazoline
s

(I
ni
: initiator, T: terminating agent, P

and P’
:
protecting group
s
)
.




21




Figure
2
.

The
terminating agents and
the
pendant chain
s

of oxazolines
bearing various elements
of the periodic table
as well as
the nature of the initiators
.



22


Figure 3.

Functionalized i
nitiators

for the cationic ring
-
opening polymerization of 2
-
R
-
2
-
oxazolines.



23




Figure

4
.

I
nitiat
ors

bearing additional
protected and unprotected
groups
.



24



Figure
5
.

Terminating agents
for
the
cationic ring
-
opening polymerization of 2
-
R
-
2
-
oxazolines.



25


Figure
6
.

R
side

groups
of

2
-
R
-
2
-
oxazoline

allowing the functionalization of POx pendant
chains
.


26



27


Figure 7.

Polyoxazo
lines bearing functional groups allowing “click chemistry” reactions (All
chemical structures were employed in “click


reactions

except

azido
-
containing polyoxazoline

with aromatic ring
, as mentioned
).



28




Figure
8
.

Chemical structure of multi
-
functionalized poly(2
-
oxazoline) allowing the
incorporation of residues by three orthogonal “click” reactions

(Diels
-
Alder, thiol
-
ene

reactions,
and azide
-
alkyne cycloaddition
.
[
128
]




29




Figure 9.

Perspectives concerning the synthesis of functionalized polyoxazolines from precursors
bearing appropriate functionality.



30

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35

Table of Contents


How to modulate chemical structure of polyoxazolines by appropriate functionalization

Brieuc Guillerm, Sophie Monge, Vincent Lapinte,* Jean
-
J
acques

Robin


Poly(2
-
oxazoline)s are widely employed as polymeric building block
for the
obtaining

of
well
defined
macromolecular architectures

for

smart applications
.
As a consequence, the
functionalization of s
uch derivatives i
s of
great
interest.
The versatility
and the diversity
of the
latter

using

functional initiator
s
, terminating agent
s

and R
pendant

chain
s

of the monomer
s

are

highlighted

in this review
.



36


Brieuc Guillerm (born in 1983 in Landerneau) obtained his Ph.D. degree in 2011 at the
University of Montpellier 2 (France), in the group of Prof. Jean
-
Jacques Robin at the

“Institut
Charles Gerhardt de Montpellier”, under the supervision of Dr. Sophie Monge and Dr. Vincent
Lapinte. His work dealt with the synthesis and physical chemistry study of amphiphilic
copolymers based on polyoxazoline. He is currently a post doctoral

researcher in the group of
Prof. Philippe Dubois at the University of Mons (Belgium). His general research interests are
now the synthesis of poly(

-
caprolactone) and polylactide, especially using organocatalyst.



Sophie Monge (born in 1975 in Toulon) o
btained her Ph.D. degree in 2000 at the University of
Montpellier 2 (France), working in the laboratory of Prof. André A. Pavia and Prof. J. P. Roque
on the synthesis of iodine
-
labeled telomers containing 2
-
nitroimidazole for the detection of
hypoxic tissu
es and tumors. Then, she was awarded a Marie Curie fellowship for a post
-
doctoral
position (two years) in the group of Prof. Dave Haddleton at the University of Warwick (UK),
working on atom transfer radical polymerization.
Sh
e joined in 2002 the laborator
y of Prof. J. J.
Robin in the “Institut Charles Gerhardt de Montpellier”. Her research interest mainly focuses on
the synthesis of well
-
defined (co)polymers with stimuli
-
responsive properties, and with polymers
bearing heteroatoms.


37


Vincent Lapinte (born

in 1973 in Tours) obtained his Ph.D. degree in 2003 at the University of
Maine (France), working in the laboratory of Prof. Laurent Fontaine on the synthesis and the
design of functionalized polymers by ring
-
opening metathesis polymerization. Then, he obt
ained
a postdoctoral position on the synthesis of p
olymers based on nitrogen
-
rich heterocycles

in the
laboratory of Dr. D. Poullain (CEA, Le Ripault), with the collaboration of Prof. F. Fontaine and
Prof J.
-
F. Pilard. H
e joined in 2004 the laboratory of Pr
of. J. J. Robin in the “Institut Charles
Gerhardt de Montpellier”. His research interest mainly covers the chemical modification and the
use of vegetable oils in polymer field as well as the polyoxazolines.



Jean
-
Jacques is a full professor of Polymer
Chemistry at the University of Montpellier 2,
(France). He received his Ph.D. degree in 1985 from the same university. His area of expertise is
the synthesis of graft copolymers and the chemical recycling of polymers. He is currently leading
the “Ingénieri
e et Architectures Macromoléculaires” laboratory of the “Institut Charles Gerhardt
de Montpellier”.